Dysfunction of the prefrontal cortex (PFC) is thought to play a key role in the neurobiology of schizophrenia. In particular, the deficit syndrome which includes negative symptoms such as anhedonia, amotivation, apathy and poverty of thought content, is attributed to PFC malfunction. Dysregulated expression of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), and other molecules regulating neuronal growth and plasticity in PFC may contribute to impaired cellular functions in schizophrenia, but the underlying molecular pathology remains unclear. Post-transcriptional and translational regulation by small RNA molecules, including microRNAs, is increasingly recognized as a key control point of gene expression and cellular functions. Presently, nothing is known about the role of microRNA-mediated regulation of gene expression during normal development of the human PFC and in chronic psychiatric disease conditions, including schizophrenia. Our preliminary data show that a subset of microRNAs predicted in silico to interact with the 3'UTR of BDNF are (i) expressed at robust levels in PFC pyramidal neurons, which comprise the primary cellular source of BDNF in cerebral cortex, (ii) are dynamically regulated during the extended course of PFC maturation and (iii) potentially dysregulated in some subjects diagnosed with schizophrenia. Guided by these preliminary findings, Aim #1 of this proposal will examine the developmental regulation and laminar and cellular expression pattern of over 20 microRNAs in human prefrontal cortex, including potential alterations in schizophrenia and regulation by antipsychotic drugs. Aim #2 will further explore the regulation of BDNF expression by the RNAi pathway in cultured cortical neurons with lentivirus-based transfection assays. Aim #3 will use a population genetics-based approach to search for BDNF regulating microRNA haplotypes that (i) might confer genetic risk for schizophrenia and related disease or (ii) affect levels of microRNA expression in PFC. It is expected that this integrative proposal, which combines postmortem studies with animal and cell culture models and clinical genetics, will provide first insights into the role of small RNAs for normal prefrontal development and chronic psychiatric disease. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major psychiatric disease, but our understanding of the underlying molecular biology and genetics remains incomplete. This research project is focused on a family of molecules called microRNAs . Very little is known about the importance of these recently discovered molecules for brain functions. We will study a subset of microRNAs that might regulate a nerve growth factor protein, in postmortem brain of subjects diagnosed with schizophrenia and controls, these studies might advance our knowledge on the biological basis of schizophrenia, and perhaps, may lead to the development of new treatment strategies for the disorder.